2-amino-4-aryl-quinolines

ABSTRACT

2-Amino-4-aryl-quinolines, e.g. those of the formula   ACYL DERIVATIVES, QUATERNARIES AND SALTS THEREOF, EXHIBIT ANTIINFLAMMATORY EFFECTS.

United States Patent Carney June 6, 1972 54] .4. ARYLQUINOLINES3,435,041 3/1969 Drukker ..260/288 v I 3,493,570 2/1970 Plostnieks......260/288 X [72] Inventor: Richard William James Carney, New

I Providence, NJ. FOREIGN PATENTS OR APPLICATIONS [73] Assignee:Ciba-Geigy Corporation, Summit, NJ. 347,515 4/1931 Great Britain..260/288 [221 P- Primary Examiner-Donald G. Daus [21] APPL No; 5,146Attorney-Harry Goldsmith, Joseph G. Kolodny and Mario A.

I Monaco Related US. Application Data [57] ABSTRACT [63]Continuation-impart of Ser. No. 638,594, May 15,

1967, p 3,542,785 2-Amino-4-aryl-qui nolines, e. g. those of the formulaR2 [52] US. Cl. ..260/286 R, 260/247.5 B, 260/268 30, 1

260/268 PH, 260/288 R R [SI] Int. Cl. ..C07d 33/52 R3 [58] Field ofSearch. .260/288, 288 A, 286, 268 HO N -flkm [56] R f ren e Cited Am=anamino or hydrazino group R =H, aliphatic, araliphatic or aromaticradical UNITED STATES PATENTS 2 aromatic radical R H, alkyl, alkoxy,alkylmercapto, halogeno, CF 3,575,984 4/1971 Plostinieks ..260/288 R MWor amino 2,086,691 7/1937 Zerweck et al. ..260/288 acyl derivatives,quatemaries and salts thereof, exhibit antiiri- 2,65 2,398 9/1953 Kaye....260/288 flammatory effects. 3,272,824 9/1966 lEibetind gee/233 6Claims, No Drawings 1. 2-AMINO-4-ARYL-QUINOLINES CROSS-REFERENCES TORELATES APPLICATIONS This is a continuation-in-part of application Ser.No 638,594, filed May 15, 1967 (now US. Pat. No. 3,542,785).

SUMMARY OF THE INVENTION The present invention concerns and has for itsobject the provision of new 2-amino-4-aryl-quinolines, more particularlythose of the Formula I DESCRIPTION OF THE PREFERRED EMBODIMENTS The1,2-phenylene radical Ph is unsubstituted or substituted by one or morethan-one of the same or different substituents attached to any of thepositions available for substitution. Such substituents, are, forexample, lower. alkyl, such as methyl, ethyl, nor i-propyl or -butyl,etherified hydroxy or mercapto, for example, lower alkoxy oralkylmercapto, such as methoxy, ethoxy nor i-propoxy or -butoxy,methylor ethylmercapto, esterified hydroxy, for example halogeno,

-such as fluoro, chloro or bromo, trifluoromethyl, nitro or amino, forexample, di-lower alkylamino, such as dimethylamino or diethylamino.Preferred l,2-phenylene radicals Ph are 1,2-phenylene, (loweralkyl)-1,2-phenylene,

(lower alkoxy)-l,2-phenylene, (lower alkylmercapto)-l,2- phenylene,(halogenol-l ,2-phenylene, (trifluoromethyl)- l ,2- phenylene,(nitro)-l,2-phenylene'or (di-lower alkylamino)- 1,2-phenylene. I

An aliphatic radical R,,' R and/or R represents especially lower alkyl,such as'methyl, ethyl, nor i-propyl, -butyl, -pentyl, -hexyl or -hepty1.R may also stand for lower alkenyl, such as allyl or methallyl,cycloalkyl or cycloalkyl-lower alkyl having from 3 to 8, especially from5 to 7, ring-carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl, cyclopropylmethyl, cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, l-cyclohexylethyl orcycloheptylmethyl. An araliphatic radical is preferably monocycliccarbocyclic aryl-lower alkyl, such as benzyl, lor 2- phenylethyl. Theseradicals are unsubstituted or contain additional substituents in thearomatic portion, such as those mentioned for Ph, and/or in thealiphatic portion hydroxy. Such radicals are, for example, hydroxy-loweralkyl, such as 2- hydroxy-ethyl, 2- or 3-hydroxypropyl, 2-, 3- or4-hydroxy-butyl.

R and R when taken together, also represent lower alkylene, aralkylene,aza-, oxaor thia-alkylene, N-(lower alkyl, hydroxy-lower alkyl orphenyl)-aza-alkylene, in which the hetero atoms are separated from eachother by at least 2 carbon atoms, such as 1,2-ethylene, l,4 -butylene,1,4- or l,5- pentylene, 3-(methyl or phenyl)-'l,5-pentylene, 2,5- or1,6- hexylene or 2,6 heptylene; 3-aza-l,5-pentylene, 3-(methyl, ethyl,2-hydroxyethyl or pheny1)-3-aza-l,S-pentylene, 3-(oxa orthia)-l,5pentylene.

An aromatic radical R and/or R and that present in the above araliphaticradical, particularly stands for monoor bicyclic carbocyclic aryl, i.e.phenyl, lor Z-naphthyl, or monocyclic heterocyclic aryl, such as furyl,thienyl or pyridyl. Said aryl groups are unsubstituted or contain one ormore than one of the same or different substituents attached to anyposition available for substitution, for example those mentioned for Ph.They primarily stand for phenyl, (lower alkyl)-phenyl, (loweralkoxy)-phenyl, (lower alkylmercapto)-phenyl, (halogeno)-phenyl,(trifluoromethyl)-phenyl, (nitro)-phenyl, (di-lower alkylamino)-phenyl,pyridyl, (lower alkyl)-pyridyl, furyl, (lower alkyl)-furyl, thienyl or(lower alkyl)-thienyl.

The acyl derivatives of the invention are particularly those ofcarboxylic acids, preferably of aliphatic, araliphatic or aromaticcarboxylic acids, such as those mentioned below, especially of loweralkanoic acids, such as acetic, propionic, butyric or pivalic acid. Thequatemaries of the invention are preferably the lower alkyl or aralkylquatemaries.

The compounds of this invention exhibit valuable pharmacologicalproperties. Apart from diuretic effects, they ex- I hibit primarilyantiinflammatory activity, as can be demonstrated in animal tests using,for example mammals, such as rats or dogs, as test objects. Such testscan be performed either according to Renzi et al., Tox. & Appl.Pharmacol. l, 406 (1959) for diuresis or according to Winter et al,Proc. Soc. Exp. Biol. & Med. 111, 544 (1962) for antiinflammatoryeffects. The compounds of the invention can be applied enterally orparenterally, e.g. orally by stomach tube, advantageously in the form ofaqueous solutions or suspensions (which may containcarboxymethylcellulose and polyethylene glycol as solubilizers), in thedosage range between about I and 75 mg/kg/day, preferably between about5 and mg/kg/day, advantageously between about 10 and 25 mg/kg/day. Inview of the test results obtained, the compounds of the invention arevaluable diuretics or antiphlogistics, advantageously in the treatmentor management of arthritic or dermatopathologic conditions. They arealso useful intermediates in the preparation of other valuable products,particularly of pharmacologically active compounds. Thus thecorresponding 2 -'amino-4-aryl-3,4-dihydro-quinolines, disclosed incopending application Ser. No. 638,593 filed May 15, 1967 (now US. Pat.No. 3,538,101) are obtained from the compounds of this invention byhydrogenation.

Particularly useful are the compounds of Formula I in which Ph is1,2-phenylene, (lower alkyl)-l,2-phenylene, (lower a]-koxy)-l,2-phenylene or (halogeno)-l,2-phenylene, R is hydrogen or loweralkyl, R is lower alkyl, lower alkenyl, cycloalkyl or cycloalkylalkylwith three to six ringand one to four chain-carbon atoms, hydroxy-loweralkyl or R lower alkyl, or R and R, together represent lower alkylene, R-lower alkylene, aza, oxaor thia-lower alkylene or N-(lower alkyl orhydroxy-lower alkyl)-aza-lower alkylene, wherein the heteroatoms areseparated from each other by at least 2 carbon atoms, R is hydrogen,lower alkyl or R and each of R,, R and R is phenyl, (loweralkyl)-phenyl, (lower alkoxy)- phenyl or (halogeno)-phenyl, ortherapeutically useful acid addition salts thereof.

Especially mentioned are the compounds of Formula II R4 a Ph XH N/ inwhich X stands for oxygen or sulfur, or preferably a reactive ester orether thereof, with a primary or secondary amine, preferably that of theformula R,NFR or b. dehydrogenating a2-amino-4-aryl-3,4-dihydro-quinoline, more particularly such of theFormula IV (IV) or c. condensing an N-( 2-aroyl-phenyl)-alkanoic oraralkanoic acid amidine, more particularly such of the Formula V d.condensing a 2-amino-B-aryl-cinnamic acid amide or nitrile, moreparticularly such of the Formula VI NH: R1

and, if desired, converting any compound obtained into another disclosedcompound.

A reactive ester of the 2-hydroxy-4-aJyl-quinoline, more particularly issuch of a hydrohalic or sulfonic acid, such as hydrochloric,hydrobromic, methane-, etharre, benzeneor ptoluenesulfonic acid. Acorresponding ether is preferably a lower alkyl or aralkyl ether. Thedehydrogenation mentioned under item (b) is preferably carried out withcatalysts, e.g. palladium catalysts, or oxidation agents, such aspotassium ferricyanide. In the reaction according to (a), (c) or (d) anywater, alcohol or mercaptan formed may either be distilled offazeotropically or absorbed by a condensing agent, such as a carbodiimid.

The compounds obtained according to said process may be converted intoother disclosed compounds by methods in themselves known. Thus, forexample, into any primary, secondary or tertiary nitrogen atom, forexample into compounds of Formula I in which R stands for hydrogen, asubstituent may be introduced, if necessary, after conversion of thecompound obtained into a metal, e.g. alkali metal, derivative thereof.This can be done, for example, by reaction with a reactive ester of anappropriate alcohol, for example, that of a hydrohalic or sulfonic acid,e.g. those mentioned above, or by reductive alkylation, i.e. reactionwith an appropriate oxocompound and subsequent or simultaneousreduction, or with an acid halide or anhydride, whereby acylderivatives, higher substituted amines or hydrazines, or quatemaries areobtained. In compounds amino-substituted by a-arylalkyl, e.g. benzyl oracyl, e.g. acetyl or phthaloyl radicals, the said radicals can be splitoff in the usual manner by hydrogenolysis, hydrolysis or hydrazinolysis.

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluents, preferably such as areinert to the reagents and are solvents thereof, of catalysts, condensingagents and/or inert atmospheres, at low temperatures, room temperatureor elevated temperatures, at atmospheric or superatmospheric pressure.Condensing agents are especially used in the reaction with said reactiveesters in order to eliminate the acid formed. They are basic agents, forexample, alkali or alkaline earth metal carbonates or lower alkoxides,or more especially, organic bases such as pyridine or collidine, butparticularly aliphatic tertiary amines, such as tri-lower alkylamines,e.g. triethylamine.

The compounds of the invention are obtained in the free form or in theform of their salts, depending on the conditions under which the processis carried out. Salts that are obtained can be converted into the freebases in known manner, for example, with alkalis or ion exchangers. Freebases that are obtained can be converted into salts by reaction withinorganic or organic acids, especially those that are suitable for theformation of therapeutically useful salts. Such acids are, for example,hydrohalic acids, e.g. hydrochloric, hydrobromic, sulfuric, phosphoric,nitric or perchloric acid, aliphatic, alicyclic, araliphatic, aromatic,or heterocyclic carboxylic or sulfonic acids, for example, fomtic,acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric,ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic,4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicyclic,aminosalicyclic, embonic, nicotinic, methanesulfonic, ethanesulfonic,toluenesulfonic, naphthalenesulfonic and sulfanilic acid; methionine,tryptophan, lysine and arginine.

These or other salts, for example, the picrates, can also be used forpurification of the bases obtained; the bases are converted into salts,the salts are separated and the bases are liberated from the salts. Inview of the close relationship between the free compounds and thecompounds in the form of their salts, whenever a free base is referredto in this context, a corresponding salt is also intended, provided suchis possible or appropriate under the circumstances.

The invention further includes any variant of the present process, inwhich an intermediate obtainable at any stage of the process is used asstarting material and any remaining steps are carried out, or theprocess is discontinued at any stage thereof, or in which the startingmaterials are formed under the reaction conditions, or in which thereaction components are used in the form of their salts. Mainly, thosestarting materials should be used in the reaction of the invention thatlead to the fonnation of those compounds indicated above as beingspecially valuable.

The starting material used in reaction (a) is prepared by condensationof N-alkanoyl or aralkanoyl-Z-aroyl-anilines or their thioderivitivesand, if desired, esterification or etherification of the resulting2-hydroxyor mercapto-4-aryl-quinoline in the customary manner, forexample with the use of phosphorus halogenides or sulfonic acid halides,or reactive esters of alcohols, such as alkyl halogenides or sulfates.The starting material mentioned under item (b) is disclosed in US. Pat.No. 3,538,101. It can be prepared analogous to reaction (c) from thealcohol corresponding to Formula V or its reactive esters or ethers, orreaction (d) from the saturated acid amide corresponding to Formula VI.The starting material mentioned under item (c) can be prepared from thecorresponding alkanoic or aralkanoic acid amide and the 2- arolyanilinein the presence of a condensing agent, e.g.

containing an effective amount thereof in conjunction or admixture withexcipients suitable for either enteral, parenteral or topicalapplication. Preferred are tablets and gelatin capsules comprising theactive ingredient together with (a) diluents, e.g. lactose, dextrose,sucrose, mannitol, sorbitol, cellulose and/or glycine, (b) lubricants,e.g. silica, talcum, stearic acid, its magnesium or calcium salt and/orpolyethyleneglycohfor tablets also (c) binders, e.g. magnesium aluminumsilicate, starch paste, gelatin, tragacanth, methylcellulo se, sodiumcarboxymethylcellulose and/or polyvinylpyrrolidone, if desired, (d)disintegrants, e.g. starches, agar, alginic acid or its sodium salt,enzymes of the binders or effervescent mixtures and/or (e) adsorbents,colorants, flavors and sweeteners. lnjectable compositions arepreferably aqueous isotonic solutions or suspensions, and suppositoriesor ointments are advantageously fatty emulsions or suspensions. They maybe sterilized and/or contain adjuvants, such as preserving, stabilizing,wetting or emulsifying agents, solution promoters, salts for regulatingthe osmotic pressure and/or buffers. Said pharmaceutical compositionsmay also contain other therapeutically valuable substances. They areprepared according to conventional mixing, granulating or coatingmethods respectively and contain about 0.1 to 75 percent, preferablyabout 1 to 50 percent, of the active in gredient.

The following examples are intended to illustrate the inven' tion andare not to be construed as being limitations thereon. Temperatures aregiven in degrees centigrade, and all parts wherever given are parts byweight.

EXAMPLE 1 The mixture of 2.5 g 2,6-dichloro-4-phenyl-quinoline and 7.5ml dimethylamine is heated in a sealed tube to 150 for 6 hours. It isthen evaporated, the residue takenup in water, the mixture extractedwith chloroform, the extract dried, filtered and evaporated in vacuo.The residue is recrystallized from ethanol to yield the2-dimethylamino-4-phenyl-6-chloro-quinoline of the formula melting atl-102.

The starting material is prepared as follows: The mixture of 30.0 g2-amino-5-chloro-henzophenone, 10. l g acetylchloride, 13.0 gtriethylamine and 250 ml benzene, is refluxed for 1 hour while stirring.After cooling it is filtered, the residue washed with benzene, thefiltrate evaporated in vacuo and the residue taken up in water. Themixture is extracted with diethyl ether, the extract washed with dilutedhydrochloric acid, dried, filtered and evaporated. The residue isrecrystallized from diethyl ether and ethanol to yield the 2-acetylamino--chloro-benzophenone melting at l l4l 17.

The mixture of 6.0 g thereof, 1.0 g sodium hydroxide, 5 ml water and 250ml ethanol, is refluxed for 30 minutes and then evaporated in vacuo. Theresidue is taken up in water, the mixture extracted with chloroform, theextract dried, filtered and evaporated. The residue is recrystallizedfrom ethanol to evaporated. The residue is recrystallized from ethanolto yield the 2,6-dicl'iloro-4-phenyl-quinoline, melting at l l3-l l5".

EXAMPLE 2 The mixture of 6.0 g 2,6-dichloro-3-methyl-4-phenylquinolineand 9.5 ml dimethylamine is heated in a sealed tube to for 2 days. It isevaporated, the residue taken up in water, the mixture extracted withdiethyl ether, the extract washed with water, dried, filtered andevaporated. The residue is recrystallized from hexane to yield the2-dimethylamino-3- methyl-4-phenyl-6chl0ro-quinoline of the formulamelting at 89-9 1.

The starting material is prepared as follows: The stirred mixture of 50g 2-arnino-5-chloro-benzophenone, 100 ml propionic acid anhydride, 0.1 gsodium acetate and 300 ml benzene is refluxed for 2 hours. After cooling100 ml water are added dropwise while stirring. The organic layer isseparated, evaporated, the residue taken up in the solution of 34 gsodium hydroxide in 50 ml water and 500 ml ethanol and the mixturerefluxed for 1 hour while stirring. It is then concentrated, the aqueousconcentrate filtered, the residue washed with water and triturated with400 ml of 6N hydrochloric acid for 5 minutes. It is filtered off, washedwith water, dissolved in chloroform, the solution treated with charcoal,filtered and evaporated. The residue is triturated with methanol andrecrystallized from methanol, to yield the 2-hydroxy-3-methyl-4-phenyl-6-chloro-quinoline melting at 257-260.

The mixture of 5.0 g thereof and 35 ml phosphorus oxychloride isrefluxed for 2 hours. After cooling, it is added dropwise to an excessof ice water while stirring. The mixture is extracted with chloroform,the extract dried, filtered and evaporated. The residue isrecrystallized from methanol to yield the2,6-dichloro-3-methyl-4-phenyl-quinoline, melting at 182-l84.

EXAMPLE 3 The mixture of 1.5 g 2,6-dichloro-3,4-diphenyl-quinoline and7.5 ml dimethylamine is heated in a sealed tube to for 6 hours. It isthen evaporated, the residue taken up in water, the mixture extractedwith chloroform, the extract dried, filtered and-evaporated in vacuo.The residue is recrystallized from hexane-benzene, to yield the 2-dimethylamino-3,4-diphenyl-6-chloroquinoline of the formula melting atl77-l79.

The starting material is prepared as follows: To the stirred mixture of50 g 2-amino-5-chloro benzophenone, 300 ml benzene, 0.1 g sodium acetateand 22 g triethylarnine, the solution of 88 g phenylacetyl chloride in50 ml benzene is added dropwise. Hereupon the mixture is refluxed for 2A hours and allowed to stand overnight at room temperature. One hundredmilliliters water are added dropwise while stirring, and the mixtureagain kept overnight. The organic layer is separated and evaporated invacuo. To the residue the solution of 34 g sodium hydroxide in 50 mlwater and 500 ml ethanol is added and the mixture refluxed for 1 hour.It is evaporated, the residue washed with water and triturated with 700ml hot 20 percent aqueous sodium hydroxide and then with 500 ml 6Nhydrochloric acid. The solid is filtered off, washed with water,dissolved in chloroform, the solution treated with charcoal, filteredand evaporated. The residue is recrystallized from methanol to yield the2-hydroxy-3,4- diphenyl-6-chloroquinoline melting at 302-305.

The mixture of 14 g thereof and 100 ml phosphorus oxychloride isrefluxed for 2 hours. After cooling, it is added dropwise to an excessof ice water while stirring. The mixture is extracted with chloroform,the extract dried, filtered and evaporated. The residue isrecrystallized from benzene-hexane to yield the2,6-dichloro-3,4-diphenyl-quinoline melting at 176-l77.

EXAMPLE 4 15 In the manner described in the previous examples, thefollowing compounds of Formula II are prepared from equivalent amountsof the corresponding starting materials of Formula ill:

R7+R5 Rt R10 R11 M.P

R7+Rs R0 R10 R11 M.P.

1r+NH5 c1115 4-cH5o c51-15 11 218221 H+C11 C5H5 4-CH30C0H4 H 1751781I+I1C3II7 H CaHi Cl 110112 +11C3H7 CeH5 CaHs Cl 149151 H-l-CHz-CH (CH HC5H5 Cl 136-138 n+ 11 @5115 Cl 165-167 H+4FC H,CIIQ C511 C511 C1 203-205II+HO-CH1-CH1 11 C5H5 Cl 146-149" 11+H0-C1L-C11z C0115 CH5 Cl 170-17311+H0-CI1 CH5 CH3 C1115 Cl 171-174" N 11+-om 11 c0115 01 115-11s CHa+CH32. H 4-CH5OC5H4 H 142145 4O 4-CH 0C5H, H 155158 C5H5 H 1l5110 C5115 117579 CsHs Cl (SS-68 OH5+OH2:CHCH2. 1 C115 C511 C1 8385 CH5+CI Iz:CI-ICH11 C5115 C5115 C1 153155 CHa-l-C5II CH2 C511 CH5 c1 150-152 C1l3-l-CaHCHz H CaHs Cl 120122 OH3+HO-CHzCH2 11 05115 C1 114 115 CH;+HOCHz-CH1 CH3C5115 Cl 125127 CH +110-c115C11- 1 C 11 C511 C1 l47150 1,5-pcntylenc n HCuHn Cl 128130 Do s s 1 s CH: CoHs Cl 143145 l)0 s 1 Cal l 5 C1115 Cl240-242 1,6-liexyl0nc 11 05115 01 129-131 50 Do CH3 Cal-I5 CI 92-94" D0C0115 CsHs Cl mil-188 C2H4-OC-H4 H C5115 Cl 120-12? 0. a. CH3 C5115 Cl155157 D0 CaH5 CuHa Cl 229231 (13115 H CoHs Cl ti l-96 C2I14-N-C2H4 Pat.No. 3698207 Folio 379 Same as above CaHr Cl 175177 Do a a t t C5115C5135 C1 227-229 C IL-CII-Cz-Hi The starting materials of the formula.

R R 1 M.P

4-CHsO-COHr ll'. 308-311 i-CliaO-Csllg l1 -103 C0115 ll 305-308 05115 ll165-167 l-CPItlO-Cali ll 235-237' 4-01130-00114 ll 154-158 C0115 11259-262" CoHs H 8587 CoHs H 231-235 00H 5 I1 -118 EXAMPLE 5 Preparationof 1000 tablets each containing 50 mg of the active ingredient:

Formula: 2-dimethylamino 4-phenyl-6-chloro-quinoline 50.0 g Colloidalsilica 2.5 g Com starch 7.5 g Magnesium stearate 1.0 g Lactose 89.0 gEthanol (anhydrous) q.s. Purified water q.s.

Procedure:

The lactose and the drug substance are passed through a comminutingmachine using a screen with 1.2 mm openings. The stearate, starch andsilica, previously mixed with a small portion of the lactose, are addedto the sieved powders, which are mixed at low speed for 30 minutes. Theyare then granulated with ethanol-water (1:1) until suitable granules areformed. The granulate is passed through a comminuting machine (knivesforward) using a screen with 4.0 mm openings. The granulate is dried at49 to a moisture content below 2 percent, again passed through acomminuting machine (knives forward) using a screen with 1.4 mm openingsand compressed into mg tablets using standard concave punches with 7.1mm diameter.

In the analogous manner tablets are prepared, each containing 50 mg ofthe 2-cyclopropylaminoor 2-piperidino-6- chloro-4-phenyl-quinoline.

EXAMPLE 6 Preparation of 10,000 tablets each containing 50 mg of theactive ingredient:

Formula: 2-dimethylamino-4-(4-methoxy-phenyl)-quinoline 500.0 g Lactose1,706.0 g Corn starch 90.0 g Polyethylene glycol 6,000 90.0 g Talcumpowder 90.0 g Magnesium stearate 24.0 g Purified water q,s.

Procedure:

All the powders are passed through a screen with an opining of 0.6 mm.Then the drug substance, lactose, talcum, magnesium stearate and half ofthe starch are mixed in a suitable mixer. The other half of the starchis suspended in 50 ml water and the suspension added to the boilingsolution of the polyethylene glycol in 50 ml water. The paste formed isadded to the powders which are granulated, if necessary, with anadditional amount of water. The granulate is dried overnight at 35,broken on a screen with 1.2 mm openings and compressed into tabletsusing concave punches with 7.1 mm diameter, uppers bisected.

EXAMPLE 7 The mixture of 1.0 g 2,6-dichloro-4-phenyl-quinoline and l 2.0g 4-fluorobenzylamine is heated in a sealed tube to 150 melting at274-276.

EXAMPLE 8 According to the method described in the previous examples,the following compounds of Formula II are prepared from equivalentamounts of the corresponding starting materials R, phenyl:

The above hydrochloride is prepared by acidifying a concentratedsolution of the base with ethanolic hydrogen chloride.

Most preferred compounds of the invention are those of Formula II,wherein R-, is hydrogen or methyl, R is methyl, ethyl, n-propyl,i-butyl, cyclopropyl or 2-hydroxyethyl, or R and R together representl,5-pentylene, 1,6-hexylene or 3- phenyl-3-aza-l,5-pentylene, R ishydrogen or methyl, R is phenyl or 4-methoxyphenyl and R is hydrogen orchlorine, or therapeutically useful acid addition salts thereof.

. 9 I claim: 1. A compound having the formula in which R, is hydrogen,methyl or ethyl, R is methyl, ethyl, n-

propyl, i-butyl, ally], cyclopropyl, cyclopropylmethyl, 2-

hydroxy-ethyl, benzyl, 4-fluoro-benzyl or 2-pyridylmethyl, or R and Rtogether are 1,4-butylene, 1,5-pentylene, 3-phenyl- 1,5-pentylene,1,6-hexylene, 3-methyl-3-aza-1,5-pentylene, 3-phenyl-3-aza-l,5-pentylene or 3-oxa-l,5-pentylene, R is hydrogen, methylor phenyl, R is phenyl or 4-methoxy-phenyl and R is hydrogen or chloro,or a therapeutically useful acid addition salt thereof.

2. A compound as claimed in claim 1, in which formula R, is hydrogen ormethyl, R is methyl, ethyl, n-propyl, i-butyl, cyclopropyl or2-hydroxyethyl, or R, and R together are 1,5- pentylene, 1,6-hexylene or3-phenyl-3-aza-l,S-pentylene, R is hydrogen or methyl, R is phenyl or4-methoxyphenyl and R is hydrogen or chlorine, or a therapeuticallyuseful acid addition salt thereof.

3. A compound as claimed in claim 1 and being the 2-dimethylamino-4-phenyl-6-chloro-quinoline or a therapeutically usefulacid addition salt thereof.

4. A compound as claimed in claim 1 and being the 2-cyclopropylamino-4-phenyl-6-chloro-quinoline or a therapeutically usefulacid addition salt thereof.

5. A compound as claimed in claim 1 and being the 2-piperidino-3-methyl-4-phenyl-6-chloro-quinoline or a therapeuticallyacceptable acid addition salt thereof.

6. A compound as claimed in claim 1 and being the 2-dimethylamino-4-(4-methoxy-phenyl)-quinoline or a therapeutically usefulacid addition salt thereof.

2. A compound as claimed in claim 1, in which formula R7 is hydrogen ormethyl, R8 is methyl, ethyl, n-propyl, i-butyl, cyclopropyl or2-hydroxyethyl, or R7 and R8 together are 1,5-pentylene, 1,6-hexylene or3-phenyl-3-aza-1,5-pentylene, R9 is hydrogen or methyl, R10 is phenyl or4-methoxyphenyl and R11 is hydrogen or chlorine, or a therapeuticallyuseful acid addition salt thereof.
 3. A compound as claimed in claim 1and being the 2-dimethylamino-4-phenyl-6-chloro-quinoline or atherapeutically useful acid addition salt thereof.
 4. A compound asclaimed in claim 1 and being the2-cyclopropylamino-4-phenyl-6-chloro-quinoline or a therapeuticallyuseful acid addition salt thereof.
 5. A compound as claimed in claim 1and being the 2-piperidino-3-methyl-4-phenyl-6-chloro-quinoline or atherapeutically acceptable acid addition salt thereof.
 6. A compound asclaimed in claim 1 and being the2-dimethylamino-4-(4-methoxy-phenyl)-quinoline or a therapeuticallyuseful acid addition salt thereof.